Esterification of carboxylic acids by reaction with o-lower alkyl imino ethers

ABSTRACT

Process for preparing an ester by reacting a carboxylic acid with an O-lower alkyl imino ether.

United States Patent Mohacsi et 211.

Apr. 1, 1975 ESTERIFICATION OF CARBOXYLIC ACIDS BY REACTION WITH O-LOWER ALKYL IMINO ETHERS Inventors: Ernest Mohacsi, Nutley; Willy Leimgruber, Montclair, both of NJ.

Assignee: Hoffman-La Roche Inc., Nutley,

Filed: May 3, 1973 Appl. No.: 356,868

US. Cl. 260/473 S, 260/338, 260/347.5, 260/404, 260/408, 260/410.9 R, 260/410.9

V, 260/468, 260/469, 260/471, 260/473 R, 260/473 F, 260/473 A, 260/474, 260/475 R, 260/476 R, 260/478, 260/483, 260/484 R, 260/485 R, 260/486 R, 260/488 F, 260/496 Int. Cl. C07c 69/78 Field of Search 260/473 R, 239 BE, 338, 260/3425, 404, 408, 410.9 R, 468, 469, 471, 473 F, 473 S, 473 A, 474, 475 R, 476 R,

[56] References Cited UNITED STATES PATENTS 2,767,182 10/1956 Konz 260/239 BE 3,510,511 5/1970 Conseiller et a1 260/496 3,700,724 10/1972 Brady 3,714,228 1/1973 Massie 260/476 R OTHER PUBLICATIONS Raber et 211., Tetrahedron Letters," 49, 4741 (1971 Grundy et 211., Tetrahedron Letters," 9, 757 (1972). March, Advanced Organic Chemistry," McGraw-Hi11,N.Y. (1968), pp. 323-324. Benson et a1., S.A.C.S., 70, 2115 (1948).

Primary Examiner-John F. Terapane Attorney, Agent, or FirmSamue1 L. Welt; Jon S. Saxe; Richard A. Gaither ABSTRACT Process for preparing an ester by reacting a carboxylic acid with an O-lower a11 y1 imino ether.

8 Claims, No Drawings ESTERIFICATION OF CARBOXYLIC ACIDS BY REACTION WITH O-LOWER ALKYL IMINO ETI-IERS BACKGROUND OF THE INVENTION This invention relates to a process for esterifying a carboxylic acid.

In the past, esterification reactions have typically involved reacting an acid with an alcohol-in the presence of a strong mineral acid, added to promote the reaction. In selected cases, the use of a strong acid provides relatively high yields of ester. However, in many other cases, the use of a strong acid medium causes significant difficulties which adversely affect the yields and purities of esters obtained by these processes. For example, using a strongly acidic medium should not be considered when either the acid or the ester is prone to acid catalyzed side reactions such as dehydration, isomerization, or hydrolysis. Furthermore, the use of a strong acid medium is not appropriate when it is desired to carry out the esterification in reaction vessels which are not specially resistant to the effects of strong acids.

In order to overcome the disadvantages of using an acid to promote esterification, processes have been developed which utilize substantially neutral reaction conditions, i.e., a pH of about 6 to 8. Such processes have typically involved reacting a carboxylic acid with an alkylating agent such as triethyloxonium fluoroborate or diazomethane. However, serious problems have also been associated with the use of such esterifying agents. Among the problems have been the high toxicity of certain agents, the explosiveness of certain agents, and/or the tendency of certain alkylating agents to decompose in the presence of moisture.

There has been a need therefore for an improved esterification procedure which provides high yields, while at the same time, allowing the reaction to be carried out under essentially neutral reaction conditions, without the acompanying problems which have heretofore been associated with alkylating agents.

SUMMARY OF THE INVENTION In accordance with this invention, a process is provided for preparing an ester, comprising reacting a carboxylic acid with an O-lower alkyl imino ether of the formula:

wherein R is an unsubstituted lower alkyl and m is an integer of from 1 to 3.

By this process, an ester can be readily prepared in high yields and with a high degree of purity under substantially neutral reaction conditions, without the use of highly toxic, explosive and/or unstable alkylating agents.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a process for preparing an ester by reacting a carboxylic acid with an O-lower alkyl imino ether of formula I. In carrying out the esteriq-(i cm) wherein n is an integer of from 1 to 4 inclusive and is equal to the valence of R and R is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl or aryl.

Among the carboxylic acid of formula II are included:

benzoic acid,

isophthalic acid,

decanoic acid,

3-methyl octanoic acid,

cyclopentanecarboxylic acid,

4-toluenecarboxylic acid,

3,5-Xylenecarboxylic acid,

l,2,3-benzenetricarboxylic acid,

l,2,4,5-benzenetetracarboxylic acid,

furoic acid,

1,8-octanedicarboxylic acid,

l,2,4,5-cyclooctanetetracarboxylic acid,

cycloeicosanecarboxylic acid,

arachidonic acid,

2,3,6,7-anthracenetetracarboxylic acid,

vitamin A acid,

ricinoleic acid,

oxalic acid,

sebacic acid,

linoleic acid,

o-chlorobenzoic acid,

m-bromobenzoic acid,

p-nitrobenzoic acid,

p-hydroxybenzoic acid,

m-methoxybenzoic acid,

m-nitrobenzoic acid,

cholanic acid,

formic acid,

acetic acid,

pivalic acid,

propionic acid,

heptanoic acid,

palmitic acid,

stearic acid,

succinic acid,

oleic acid,

fumaric acid,

maleic acid,

cyclopentenylacetic acid,

cyclohexylpropionic acid,

phenylacetic acid,

naphthylpropionic acid, and

napthoic acid.

Among the preferred carboxylic acids of formula II are the compounds of the formula:

wherein n is an integer of from 1 to 2 and R is unsubstituted alkyl, unsubstituted alkenyl, aryl, aryl lower alkyl or aryl lower alkenyl.

Particularly preferred are the carboxylic acids of the formula:

wherein R," is unsubstituted lower alkyl, carboxy lower alkyl, unsubstituted lower alkenyl, unsubstituted aryl, lower alkoxy or hydroxy substituted aryl, unsubstituted aryl lower alkyl, lower alkoxy or hydroxy substituted aryl lower alkyl, unsubstituted aryl lower alkenyl, or lower alkoxy or hydroxy, substituted aryl lower alkenyl.

As also used throughout this application, the term alkyl comprehends straight chain and branched chain, saturated aliphatic hydrocarbon groups of l to carbon atoms. The alkyl groups of this application may be unsubstituted or substituted with one or more groups such as alkoxy, alkenyloxy, alkynyloxy, hydroxy, oxo, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, cycloalkenyloxy, cycloalkynyloxy and aryl groups. In this application, the preferred alkyl groups are the unsubstituted lower alkyl groups of l to 6 carbon atoms, such as-methyl, ethyl and isopropyl. With regard to the unsubstituted lower alkyl groups represented by R in formula I, the particulary preferred alkyl groups are the primary and secondary, unsubstituted, lower alkyl groups, quite particularly methyl and ethyl.

Also throughout this application, the term cycloalkyl comprehends saturated, aliphatic hydrocarbon groupgs of 3 to 20 carbon atoms, containing one or more, saturated, mononuclear or polynuclear, cycloaliphatic moieties, such ascyclopropyl and cyclohexyl.

Also in this application, the term alkenyl comprehends straight chain and branched chain, aliphatic hydrocarbon groups of 2 to 20 carbon atoms which contain one or more double bonds. The alkenyl groups of this application can be unsubstituted or substituted with one or more groups, such as alkoxy, alkenyloxy, alkynyloxy, hydroxy, oxo, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, cycloalkenyloxy, cycloalkynyloxy and aryl groups. In this application, the preferred alkenyl groups are the unsubstituted lower alkenyl groups of 2 to 6 carbon atoms such as vinyl and allyl.

Also herein, the term cycloalkenyl" comprehends aliphatic hydrocarbon groups of 3 to 20 carbon atoms containing one or more, mononuclear or polynuclear, cycloaliphatic moieties, of 3 to 18 carbon atoms, with at least one of the cycloaliphatic moieties containing one or more double bonds, such as cyclohexenyl.

As further used throughout this application, the term alkynyl comprehends straight chain and branched chain, aliphatic hydrocarbon groups of 2 to 20 carbon atoms which contain one or more triple bonds. The alkynyl groups of this application can be unsubstituted or substituted with one or more groups, such as alkoxy, alkenyloxy, alkynyloxy, hydroxy, oxo, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, cycloalkenyloxy, cycloalkynyloxy and aryl groups. In this application, the preferred alkynyl groups are the unsubstituted lower alkynyl groups of 2 to 6 carbon atoms, such as ethynyl and propynyl.

Further throughout this application, the term cycloalkynyl" comprehends aliphatic hyrdocarbon groups of 3 to 20 carbon atoms containing one or more, mononuclear or polynuclear, cycloaliphatic moieties,

with at least one of the cycloaliphatic moieties containing one or more triple bonds, such as cyclohexynyl.

Further herein, the term aryl comprehends mononuclear and polynuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc., which can be unsubstituted or substituted in one or more positions, taken individually or together, with groups such as lower alkylenedioxy, halogen, nitro, alkoxy, alkenyloxy, alkynyloxy, alkyl, alkenyl, alkynyl, cycloalkenyloxy, cycloalkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, hydroxy and 0x0 groups. Among the polynuclear aryl groups are groups such as napthyl, anthryl, phenanthyl, azulyl, etc., which may be unsubstituted or substituted with one or more of the aforementioned moieties. In this application, the preferred aryl groups are the unsubstituted aryl groups and the aryl groups, substituted with a hydroxy or lower alkoxy group, containing 6 to 10 carbon atoms.

As still further used throughout this application, the term primary alkyl group comprehends groups wherein alkyl is as defined above and wherein the a-carbon atom of the group is a primary carbon atom. Also herein, the term secondary alkyl group" comprehends groups wherein alkyl is as defined above and wherein the a-carbon atom of the group is a secondary carbon atom.

Still further herein, the term halogen or halo when not expressly stated otherwise, includes all four halogens, i.e., chlorine, bromine, fluorine and iodine. The term lower alkylenedioxy comprehends groups having 1 to 4 carbon atoms such as methylenedioxy.

As still further used herein, the terms alkoxy, alkenyloxy, a]kynyloxy,cycloalkoxy, cycloalkenyloxy and cycloalkynyloxy comprehends the groups wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties are as defined above. Still further herein, terms such as aryl lower.

alkyl, aryl lower alkenyl, and carboxy lower alkyl comprehend alkyl and alkenyl groups which are substi-.

tuted with only an aryl group or a carboxy group and wherein the alkyl and aryl moieties are as defined above.

In carrying out the process of this invention, temperature and pressure are not critical, and the reaction can be conveniently carried out at above about 40C. and at atmospheric pressure. Preferably, the reaction is carried out at a temperature of about 60C. to the reflux temperature of the reaction mixture, with a temperature of about to C. being particularly preferred.

In carrying out this process, any carboxylic acid can be utilized, and the ratio of the carboxylic acid to the O-lower alkyl imino ether of formula I is not critical. In this process, it is preferred to utilize at least 1 mole equivalent of the O-lower alkyl imino ether'for each mole equivalent of carboxylic acid, with about 1 mole equivalent of each reactant being particularly preferred. However, if desired, greater amounts of the lower alkyl imino ether canals'o be conveniently utilized. r i

This process can, if desired, be carried out in an inert organic solvent. In this process, any conventional inert organic solvent can be utilized, such as benzene, toluene, methylene chloride or chloroform..Preferably, the

tered off, and the filtrate was concentrated. The crude ester was purified by crystallization if the ester was a solid, utilizing an appropriate solvent, or by distillation under reduced pressure if the ester was a liquid to give analytically pure material.

The table which follows summarizes. the results of the example.

Table of Esterification of Carboxylic Acids with O-Methylcaprolactim Conditions Methyl ester Carboxylic Acid Temp.C. Time, hr. Yieldffi B.p. or M.p.C.

Benzoic acid 80-85 [6 9| B.p. l0l-l02/24mm p-Methoxyphenyl acetic acid 80-85 6 76 "B.p. ISO-l l/l 5mm 2-Naphthoic acid 80-85 l6 )6 M.p. 75-76 Adipic acid 80-85 16 72 B.p. 95/9mm Dimethyl acrylic acid 80-85 16 78 B.p.= l-l35 Salicylic acid 80-85 16 8O B.p. 87-88/7mm p-Methoxycinnamic acid 80-85 16 73 M.p. 88-90 Residue after diethyl ether removed by distillation. Crystallization not required.

(rystallized from ethanol.

Based on isolated material.

process of this invention is carried out without utilizing any solvent, using only the carboxylic acid and the 0- alkyl imino ether of formula I.

EXAMPLE 2 Utilizing the procedure of Example 1, O-lower alkyl By the process of this invention, yields of about 70 to 25 imino ethers were reacted with benzoic acid. The table 90 percent of the ester can be obtained. The ester which follows summarizes the results obtained.

Table of Esterification of Benzoic Acid by O-alkyl imino ethers Molar ratio of Yield of imino ether to Temp. Time isolated methyl imino Ether Benzoic Acid C. Hr. benzoate Z-methoxyl -pyrroline 2 85-90 20 78 2-methoxy-3,4,5,6- tetrahydropyridine 1 85-90 24 70 O-methylcaprolactim 2 85-90 20 92 which is produced by this process can be readily separated from the water soluble by-product of the process, i.e., a lactam of the formula:

III ng EXAMPLE 1 A carboxylic acid (0.] mol) and O- methylcaprolactim (0.1 mol per carboxyl group in the acid) were heated at 80to 85C. from 6-16 hrs. The resulting liquid was diluted with diethyl ether, washed with 1N aqueous sodium hydroxide solution, washed with water, and dried over MgSO The MgSO was fil- What is claimed is:

1. A process for preparing an ester comprising: reacting a carboxylic acid with an O-lower alkyl imino ether of the formula:

wherein R is an unsubstituted lower alkyl and m is an integer of 1 to 3; wherein said carboxylic acid is of the formula:

wherein n is an integer of from 1 to 4 inclusive and-is equal to the valence of R and R is hydrogen, substituted or unsubstituted alkyl having from 1 to 20 carbon atoms, cycloalkyl having from 3 to 20 carbon atoms, unsubstituted or substituted alkenyl having from 2 to 20 carbon atoms, cycloalkenyl having from 3 to 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to 20 carbon atoms, cycloalkynyl having from 3 to 20 carbon atoms, unsubstituted or substituted aryl selected from the group consisting of phenyl, naphtyl, anthryl, phenanthyl and azulyl 2. The process of claim 1 wherein said process is carried out at about 60C. to the reflux temperature of the reaction mixture.

3. The process of claim 2 wherein said process is carried out at about 80 to 85C.

4. The process of claim 1 wherein at least about one mol of said O-lower alkyl imino ether is utilized per mol equivalent of said acid.

5. The process of claim 1 wherein said O-lower alkyl imino ether is an O-alkylcaprolactim.

6. The process of claim 5 wherein R is methyl or ethyl.

7. The process of claim 1 wherein said carboxylic acid is of the formula:

wherein n is an integer of from 1 to 2 and R is unsubstituted alkyl, unsubstituted alkenyl, aryl, aryl lower alkyl or aryl lower alkenyl.

8. The process of claim 7 wherein said carboxylic acid is of the formula:

Inventofls) Patent No. 3 875 209 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Dated Ami] 1 ILQ'ZR ERNEST MOHACSI AND WILLY LEIMGRUBER It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

On first page, "Assignee:

Hoffman-La Roche Inc.."

should be nee: Hoffmanm-La Roche Ino.

Signed and Sealed this tenth Day of February 1976 [SEAL] A tres t.-

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner vfParents and Trademarks 

1. A PROCESS FOR PREPARING AN ESTER COMPRISING: REACTING A CARBOXYLIC ACID WITH AN O-LOWER ALKYL IMINO ETHER OF THE FORMULA:
 2. The process of claim 1 wherein said process is carried out at about 60*C. to the reflux temperature of the reaction mixture.
 3. The process of claim 2 wherein said process is carried out at about 80* to 85*C.
 4. The process of claim 1 wherein at least about one mol of said O-lower alkyl imino ether is utilized per mol equivalent of said acid.
 5. The process of claim 1 wherein said O-lower alkyl imino ether is an O-alkylcaprolactim.
 6. The process of claim 5 wherein R is methyl or ethyl.
 7. The process of claim 1 wherein said carboxylic acid is of the formula:
 8. The process of claim 7 wherein said carboxylic acid is of the formula: 